This invention relates to methods of preparing pressure sensitive adhesive matrix layers for transdermal drug delivery.
The delivery of drugs through the skin provides many advantages. Primarily, it is a comfortable, convenient and non-invasive way of administering drugs. Moreover, such a means of delivery provides for uninterrupted therapy and a higher degree of control over drug concentrations in the blood.
Transdermal delivery of various active pharmaceutical ingredients (“API”) and pressure sensitive adhesive matrix patches for transdermal delivery of such APIs are well known in the art of drug delivery. These matrix patches include a pressure sensitive adhesive layer for affixing the patch to the skin and for carrying the API and any excipients that are directly incorporated into this adhesive layer into the body. These adhesive matrix patches also typically include an inert backing layer to provide support, and a release liner which covers and protects the adhesive. The release liner is peeled off and discarded before applying the patch to the skin. These patches are distinguished from reservoir patches in that the API in a reservoir patch is incorporated in a layer or compartment, with a differing material composition, separate from the pressure sensitive adhesive layer. One type of adhesive commonly used in the adhesive layer is polyisobutylene (“PIB”).
When such adhesives are used in transdermal delivery devices it is necessary that they exhibit a reasonable permeability to the API being delivered and, when they are used in combination with a rate-controlling membrane, the adhesive layer preferably exhibits a higher permeability to the API than the rate controlling membrane.
Mixtures of high and low molecular weight PIBs are known in the art as adhesives, however they are relatively impermeable to many APIs. As a result, the prior art PIB adhesives usually contain a plasticizer such as mineral oil (“MO”) or polybutene to achieve sufficient permeability to permit API migration through the adhesive at rates which are therapeutically useful from reasonably sized systems.
For example, U.S. Pat. No. 4,559,222 is directed to compositions comprising PIB in conjunction with copious amounts of mineral oil to deliver the active agent clonidine. In particular, the systems described use a ratio of mineral oil to PIB of at least 1.0, and preferably higher amounts, in the API delivery matrix. Here, the mineral oil acts to plasticize the adhesive and to increase the permeability of the adhesive composition to the API.
U.S. Pat. No. 5,508,038 is directed to an adhesive which is useful as an adhesive in transdermal delivery devices. The adhesive comprises mixtures of high molecular weight (“HMW”) and low molecular weight (“LMW”) PIBs in weight ratios of about 5-40 HMW PIB: 95-60 LMW PIB which are substantially free of plasticizers and tackifiers. The system is processed by solvent coating the mixture of PIBs and API onto a release liner and then evaporating the solvent from the API/PIB adhesive matrix. The process is limited to a batch of solvated PIB and API, as well as limited by the necessity and cost of evaporating solvent from the adhesive matrix. Moreover, in the case of highly volatile APIs, it is difficult to evaporate the solvent without also evaporating at least part of the API.
U.S. Pat. No. 6,365,178 is directed to a method of making a pressure sensitive matrix patch for transdermal delivery of an API. The method includes the steps of dissolving a hydrophilic salt form of an API in a water phase of an aqueous dispersion of a hydrophobic pressure sensitive adhesive, casting the resulting mixture as a thin film, and evaporating the water. Similar to U.S. Pat. No. 5,508,038 described above, PIB in a solvent is used to coat a release liner.
U.S. Pat. No. 6,555,130 describes the use of a twin screw extruder to make a continuous film of adhesive/API. The patent, however, discloses only the use of granulated PIB which necessitates a filler or coating material, such as talc, to prevent agglomeration of the granulated PIB. Not only does the granulation step and incorporation of filler materials add costly processing steps, it also complicates the final formulation and could negatively impact chemical stability or physical properties.
The art described thus far involves either solvent coating the FIB and API or the use of excipients, such as mineral oil, to vary the rate of API release. It is desirable, however, to substantially eliminate the use of solvents or the use of such excipients.
The advantage of foregoing the use of solvents lies essentially in the simplification of the coating process. The avoidance of flammable solvents does away with the need for drier units, with their high energy consumption, for the evaporation and recovery of the solvents, and with the need to use explosion-protected units. Hot-melt coating units are compact and permit much higher coating speeds. The technology is environmentally-friendly, with no solvent emissions. Furthermore, no unwanted solvent residues remain in the self-adhesive composition.